Note that use of the drugs did not appear to have any long-term impact on function and were associated with harms -- including diarrhea, nausea and vomiting.

Four widely prescribed Alzheimer's drugs failed to improve cognition or function in patients with mild cognitive impairment and were even associated with harms -- including diarrhea, nausea and vomiting, according to a meta-analysis.

No significant improvements in cognition were seen with the cognitive enhancing drug, as measured by the Mini-Mental State Examination (three trials of donepezil, mean difference [MD] 0.14, 95% CI: -0.22 to 0.50) and the Alzheimer's Disease Assessment Scale cognition subscale (three trials, standardized MD -0.07, 95% CI -0.16-0.01), Andrea C. Tricco, PhD, of St. Michael's Hospital in Toronto, Ontario, and colleagues, wrote in CMAJ.

And use of the drugs did not appear to have any long-term impact on function, as measured by the Alzheimer's Disease Cooperative Study activities of daily living inventory (two trials, MD 0.30, 95% CI -0.26-0.86).

"These cognitive enhancers did not help patients with mild cognitive impairment, which is characterized by memory complaints and limitations in day-to-day activities, and their use was associated with harm," Tricco told MedPage Today.

The findings are similar to those of another meta-analysis, published last year by reviewers for the Cochrane Collaborative.

In that review, which did not include studies evaluating memantine, researchers concluded that there was "very little evidence" that the cholinesterase inhibitors donepezil, galantamine or rivastigmine prevented progression to dementia over 3 years of follow-up. Patients with mild cognitive impairment who took them also reported more side effects, including nausea and vomiting, diarrhea, leg cramps and abnormal dreams.

Memantine is the only NMDA receptor antagonist approved for the treatment of Alzheimer's disease, and the new analysis included a small (60-patient) 2007 double-blind study comparing the drug to placebo.

Two studies included in the new analysis evaluated patients taking galantamine (990 and 1058 patients), four evaluated patients on donepezil (51, 269, 512 and 757 patients) and one (1014 patients) evaluated rivastigmine.

Among the findings:

No significant difference in cognition was seen, as measured by the Alzheimer's Disease Assessment scale, between donepezil or galantamine and placebo after a median of 24 weeks of follow-up (five trials, standardized MD -0.07, 95% CI -0.16-0.10).

For follow-up periods ranging from 6 to 156 weeks, a significant trend was seen in the meta-regression analysis, with results showing statistical significance in favor of the drugs over placebo for studies providing data after 12 to 84 weeks' follow-up (1531 patients), but not for studies providing data after 85 to 96 weeks of follow-up (1901 patients).

After 96 weeks of follow-up, no significant difference in functional status was seen, as measured by the Alzheimer's Disease Cooperative Study activities of daily living inventory, among patients who received galantamine and those who received placebo.

No significant difference in overall mortality was seen among patients taking the dementia drugs and those in the placebo arm after a median of 156 weeks (3 trials, relative risk 1.84, 95% CI 0.41-8.20).

The frequency of nausea and diarrhea was significantly greater among patients taking donepezil, rivastigmine or galantamine than among those taking placebo after a median of 126 weeks of follow-up (nausea: four trials, RR 3.04, 95% CI 2.52-3.66; diarrhea: four trials, RR 2.33, 95% CI 1.74-3.13).

No significant difference in serious adverse events was seen between all four of the dementia drugs and placebo after 48 weeks of follow-up, but only one study defined serious adverse events as a medical occurrence that included death.

"These trials did not include enough information about these harms and we really don't know if these drugs impact mortality based on what has been reported," Tricco said.

The researchers concluded that the results do not support the use of cognitive enhancing drugs for patients with mild cognitive impairment.

"Patients and their families should consider this information when requesting these medications," co-author Sharon Straus, MD, noted in a statement. "Similarly, health care decision-makers may not wish to approve the use of these medications for mild cognitive impairment, because these drugs might not be effective and are likely associated with harm."

Tricco and several coauthors reported links with the Canadian Institutes for Health Research.

Straus is an associate editor for CMAJ. She was not involved in the editorial decision-making process for this article.

Reviewed by Robert Jasmer, MD Associate Clinical Professor of Medicine, University of California, San Francisco

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